PB2238: ΒETA-THALASSEMIA INTERMEDIA: INTERACTION OF ΑLPHA-GLOBIN GENE TRIPLICATION WITH ΒETA-THALASSEMIA HETEROZYGOUS IN SPAIN
Authors: P. Ropero, F. A. González, J. M. Nieto, W. M. Torres-Jiménez, B. Colas, P. Estival, A. Calo, S. Escribano, S. Rochas, A. Villegas, C. Benavente, G. E. de Eritropatología
Journal: HemaSphere (2022)

Background: The spectrum of β-thalassemias is broad, ranging from β-thalassemia major (β-TM), to mild forms known as β-thalassemia minor, and intermediate forms [β-thalassemia intermediate (β-TI)]. Although β-TI lacks specific molecular correlates and diagnosis remains largely clinical, a genotype/phenotype association has been described such that genetic modulators determine the genetic basis of phenotypic diversity. Other genetic modulators are those that are directly involved in the imbalance of the β-globin chains. Homozygosity or double heterozygosity with overexpression of γ-globin chains, either because one or both alleles correspond to a δβ-thalassemia, or because they are associated with molecular alterations in the same or a different one, result in increased γ-globin chain synthesis. Also, the increased production of α-globin chains by a triplication or quadruplication of α genes (ααα/αα or αααα/αα) associated with a heterozygous β-thalassemia is a β-TI. Aims: To verify with hematimetric data that the diagnosis and clinical grade of β-TI can be established when a triplication of alpha genes (αααanti 3.7) and heterozygous β-thalassemia coexist. Methods: Retrospective study from January 2010 to December 2019 and involved 73 patients of Caucasian origin with triplication or quadruplication of α-genes and β-thalassemia. Screening the most frequent α-thalassemia mutations as well as gene triplication (αααanti 3.7) was carried out with a commercial Alpha-Globin StripAssay kit and confirmed by MLPA. Molecular diagnosis of β-thalassemia was performed by automatic Sanger sequencing. Results: The genotypes have been classified into three groups according to the number of α globin genes and the severity of the alteration in the β globin gene. All had a mutation in the HBB gene (β0-thalassemia, severe β+-thalassemia, and mild β+-thalassemia). Group I patients who have coherent 6 α genes and groups II and III with 5 α globin genes. In group III, the patients were carriers of mutations affecting the β and δ globin genes [(δβ)0-Spanish Thalassemia]. The most significant hematological parameters were hemoglobin levels, MCV, RDW, and the percentage of Hb F (Table). Image:Summary/Conclusion: This study has provided the largest series of patients with heterozygous β-thalassemia associated with α-globin gene triplication. These data showed that the effect of the association of the α-globin gene triplication with a heterozygous β-thalassemia mutation is highly variable. In group I, regardless of the distribution of the 6 α-globin genes, homozygous triplication (ααα/ααα) or heterozygous quadruplication (αααα/αα), association with heterozygous β-thalassemia results in anemia of moderate to severe that may or may not require transfusion therapy, it is the severity of the HBB gene mutation that would determine the clinical variation. Group II patients behaved phenotypically as mild thalassemia intermedia. Finally, group III patients behaved as a thalassemia trait since all of them were carriers of mutations that increase the overexpression of γ genes. The phenotype could be established through the most significant hematological parameters 1) hemoglobin levels, 2) MCV, 3) RDW and 4) the percentage of Hb F. But molecular diagnosis and genetic counseling should continue to be used because, although the heritability of a triplication of alpha genes, in many cases underdiagnosed, does not present clinical complications, it can be inherited with another pathology such as heterozygous β-thalassemia and aggravate the clinical picture.